The European Pharmacopoeia Commission has adopted a new general chapter for the analysis of N-nitrosamine impurities in active substances.
The chapter is considered an analytical toolbox that relies on three procedures using GC-MS, LC-MS/MS and GC-MS/MS. A varied set of procedures using different instruments were used to cover the diverse needs of many quality control laboratories in Europe and beyond.
The procedures have been validated for the listed active substances either as a limit test with a target concentration of 30 ppb, or as a quantitative test. The primary focus is the analysis of N-nitrosamine impurities in angiotensin-II-receptor antagonists containing a tetrazole group (i.e. valsartan, losartan potassium, candesartan cilexetil, irbesartan and olmesartan medoxomil). The given procedures can be applied to other substances or to medicinal products, provided that they can demonstrate the suitability for the intended purpose with additional validation. Depending on the analytical challenge and the testing needs, other validated procedures may be more appropriate.
A total of seven N-nitrosamine impurities are covered in three procedures: N-nitroso-dimethylamine (NDMA), N-nitroso-diethylamine (NDEA), N-nitroso-dibutylamine (NDBA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-diisopropylamine (NDiPA), N-nitroso-ethyl-isopropylamine (NEiPA) and N-nitroso-dipropylamine (NDPA).
Seven reference standards have been established and are available from the European Directorate for the Quality of Medicines & HealthCare (EDQM). They will be published in the European Pharmacopoeia Supplement 10.6 in July 2021.
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